As the most common inherited blood disorder, sickle cell disease (SCD) affects one in 400 African-Americans. The disorder alters the shape of the red blood cell, leading to systemic, multi-organ effects, reducing the median life expectancy to 40 years. Among its complications, ischemic stroke is common and disabling, beginning in infancy - overt strokes cause acute neurological deficits and silent strokes manifest as intellectual decline. A screening method to prevent strokes, transcranial Doppler ultrasound (TCD), is helpful for selecting SCD children who will benefit from transfusion therapy as a means to reduce stroke occurrence. Unfortunately, however, the screening mechanism has several limitations including its insensitivity for predicting those at risk for silent strokes. Moreover, nearly half of children continue to have recurrent overt strokes, silent strokes, and/or progressive vasculopathy, despite screening and being placed on transfusions. Thus, an improved biomarker for stratifying stroke risk in SCD children is needed. In this proposal, we hypothesize that the brain's hemodynamic and metabolic compensatory responses to reduced blood oxygen content in SCD will reveal mechanisms leading to ischemic stroke. We will determine if MR-derived cerebral blood flow (CBF) and oxygen extraction fraction (OEF), as metrics of this hemodynamic and metabolic stress, may provide novel tools to stratify stroke risk in SCD children so that treatment may be individualized, identifying those at highest risk for more aggressive therapies, while sparing those at lower risk any unnecessary adverse effects of treatment. We hypothesize that measurements of CBF and OEF at the brain- tissue level will be more sensitive and specific for stroke risk than blunt measures of blood velocity as measured by TCD. Over the past 15 years, we have developed a novel, noninvasive MR approach to measure brain OEF at the voxel-level. Until now, OEF could only be measured by PET imaging, and thus has never been studied in SCD children due to the risks of radiation. Aim1. To determine if CBF and OEF are increased in SCD children compared to sibling controls indicating an elevated stroke risk. Aim2. To determine if hemispheric CBF and OEF demonstrate greatest alteration in the subset of SCD children with vasculopathy indicating a very high risk of stroke in the territory of the affected vessel. Aim3. To determine if transfusion therapy normalizes CBF and OEF, thereby reducing hemodynamic and metabolic stress as a means to reduce stroke risk. Aim 4. To determine if elevated CBF and/or OEF predict future stroke on 3 year follow-up MRI better than TCD.